Boost Your Cancer Immunotherapy: How Common Antihistamines May Improve Treatment Success

Vikas P. Sukhatme, MD, ScD

Introduction

In recent years, a surprising discovery has emerged in cancer care: common over-the-counter antihistamines, specifically those targeting histamine receptor H1 (HRH1), may significantly improve how well patients respond to immunotherapy treatments. This finding could potentially transform outcomes for patients receiving immune checkpoint inhibitors (ICIs) like PD-1/PD-L1 blockers, which have revolutionized cancer treatment but still fail to help many patients.

What the Research Shows

Multiple studies examining thousands of cancer patients have consistently demonstrated that patients who took H1 antihistamines (commonly used for allergies) during immunotherapy treatment had significantly better survival rates compared to those who did not take these medications.

  • In melanoma patients, Li et al. (2022) found that those taking H1 antihistamines during anti-PD-1/PD-L1 treatment had a significantly reduced death rate (30% vs 50%) compared to matched patients who did not take antihistamines.
  • In lung cancer patients, a similar pattern emerged with a 58% death rate in patients not taking antihistamines versus 40% in those who did (Li et al., 2022). Additionally, Zhang et al. (2024) documented that the median progression-free survival was 12.7 months in patients receiving H1 antihistamines compared to just 4.3 months in the control group.
  • In bladder cancer patients, Fallara et al. (2025) reported that concomitant antihistamine administration was associated with longer overall survival (OS), progression-free survival (PFS), and cancer-specific survival (CSS) in patients receiving atezolizumab(a PD-L1 antibody) as second-line treatment.
  • In laboratory studies, researchers found that histamine in the tumor microenvironment can induce T cell dysfunction by activating HRH1 on macrophages, pushing them toward an immunosuppressive state. H1 antihistamines reversed this effect, restoring T cell function and enhancing immunotherapy response (Li et al., 2022).

Notably, the benefit of antihistamines appears specific to immunotherapy treatments. When examining patients receiving chemotherapy alone, the survival advantage of taking antihistamines disappeared (Li et al., 2022), suggesting that antihistamines specifically enhance immune-mediated cancer control.

Why Timing Matters: The Science Behind Histamine's Effects

The mechanism behind this phenomenon has been thoroughly investigated. Histamine, a mediator best known for its role in allergic reactions, appears to play an unexpected role in cancer immunology:

  • Cancer cells produce histamine: Many tumor types produce elevated levels of histamine, which acts as an immunosuppressive signal in the tumor microenvironment (Li et al., 2022).
  • Histamine affects immune cells: When histamine binds to HRH1 receptors on macrophages (a type of immune cell), it causes them to adopt an immunosuppressive "M2-like" state and upregulate a protein called VISTA, which inhibits T cell function (Li et al., 2022).
  • T cell dysfunction: This leads to dysfunction of cytotoxic T cells, the primary cell type responsible for killing cancer cells during immunotherapy.
  • H1 antihistamines block this pathway: By preventing histamine from binding to HRH1, these drugs help maintain proper immune function, allowing immunotherapy drugs to work more effectively.

H1 vs. H2 Antihistamines: An Important Distinction

Interestingly, not all antihistamines provide the same benefit. While H1 antihistamines (like fexofenadine, loratadine, cetirizine) appear to enhance immunotherapy, H2 antihistamines (like ranitidine, famotidine, cimetidine) may actually have detrimental effects:

  • Zhang et al. (2024) reported that patients who received H2 antihistamines (cimetidine) during immunotherapy had shorter progression-free survival and overall survival compared to patients who did not.
  • In their study, patients treated with only H1 antihistamines had significantly better median progression-free survival (18.0 months) compared to those who received H1 plus H2 antihistamines (6.8 months).
  • Fallara et al. (2025) similarly found that H2 antihistamines were associated with a 2.38-fold higher risk of mortality in bladder cancer patients treated with immunotherapy.

These findings suggest that different classes of antihistamines interact differently with immunotherapy mechanisms, highlighting the importance of the specific type of antihistamine used.

Questions and Considerations

While the evidence is compelling, several questions remain:

  • Optimal dosage and timing: Most studies to date have examined patients who were taking standard doses of antihistamines for allergies or to prevent infusion reactions. The optimal dosing schedule for maximizing immunotherapy efficacy has not been established.
  • Which patients benefit most: Whether all patients would benefit equally from adding antihistamines to immunotherapy or if certain biomarkers (such as plasma abnormally high histamine levels) could identify those most likely to benefit requires further study.  In Li et al. (2022), patients across multiple tumor types with plasma levels exceeding 0.6 ng/ml showed the worst response to immunotherapy.
  • Randomized clinical trials: Most evidence to date comes from retrospective analyses and animal studies. While these data are persuasive, large-scale randomized clinical trials would provide definitive evidence.

What This Means for Patients

If you or a loved one is undergoing immunotherapy for cancer, these findings suggest a potentially simple way to improve treatment outcomes:

  1. Discuss H1 antihistamines with your oncologist: Ask whether adding an H1 antihistamine (like loratadine or desloratadine (the latter preferred), fexofenadine, or cetirizine) during your immunotherapy treatment might be appropriate for you, perhaps based upon a high plasma histamine level.
  2. Avoid H2 antihistamines if possible: Based on current evidence, H2 blockers (used for heartburn and acid reflux) might reduce immunotherapy effectiveness.

This strategy is particularly appealing because H1 antihistamines are generally safe, well-tolerated, inexpensive, and widely available. Adding them to immunotherapy requires no new drugs or complex procedures—just a simple medication that might significantly improve your treatment outcomes.

References

  1. Li H, Xiao Y, Li Q, et al. The allergy mediator histamine confers resistance to immunotherapy in cancer patients via activation of the macrophage histamine receptor H1. Cancer Cell 2022;40:36-52.
  2. Zhang WH, Li BX, Ma CX, et al. Association of concomitant H1 antihistamine and immune checkpoint inhibitor therapy on survival outcome and safety in patients with advanced primary lung cancer: a cohort study. Transl Lung Cancer Res 2024;13(10):2787-2801.
  3. Fallara G, Belladelli F, Robesti D, et al. Concomitant antihistamine administration is associated with improved survival outcomes in patients with locally advanced or metastatic urothelial carcinoma treated with atezolizumab. Analysis of individual participant data from IMvigor210 and IMvigor211. Urol Oncol 2025;43:188.e9-188.e17.
  4. Fritz I, Wagner P, Olsson H. Improved survival in several cancers with use of H1-antihistamines desloratadine and loratadine. Transl Oncol 2021;14:101029.
  5. Fritz I, Wagner P, Broberg P, et al. Desloratadine and loratadine stand out among common H1-antihistamines for association with improved breast cancer survival. Acta Oncol 2020;59:1103-1109.
  6. Eylemer Mocan E, Yekedüz E, Karataş G, et al. Impact of antihistamine use on the survival outcomes of immune checkpoint inhibitors in advanced cancer patients. Anticancer Drugs 2024;35:190-194.